A bacterial pathogen must be able to invade and subsequently multiply, or at least survive in its host. Normally, the host defenses, such as serum-killing and phagocytosis, successfully oppose the invader. Where an infection becomes established, administration of antibiotics may provide additional time for the host to marshall its defenses eliminate invading pathogen. These studies focus on how the cell surface components of pathogenic function in resistance to host defense mechanisms and antibiotics. A) Resistance to serum killing phagocytosis. Both capsular polysaccharide and 0-antigen polysaccharide of lipopolysaccharide (LPS) have a role in the survival of the Salmonellae in the host. The specific structure of the LPIS O-antigen is responsible for the rate and extent of complement activation which, in turn, is responsible for the serum-killing of the cell. The Vi-- antigen of Salmonella typhi is a surface capsular polysaccharide that has long been postulated to provide protection against host defenses. Using isogeneic pairs of Salmonellae strains differing only in the presence of absence of the Vi-antigen, we have shown that the Vi-antigen provides protection against phagocytosis but not serum-killing. B) Escherichia coli and other Gram-negative bacteria grown in the presence of salicylate or aspirin become phenotypically resistant to a variety of commonly used antibiotics including cephalosporins, norfloxacin, and tetracycline. This resistance often extends beyond the levels usually achieved during antibiotic therapy is due, at least in part, to surface alterations that reduce the permeation of the anabiotic into the cell. These changes extend to bacteria grown in serum. These observations may contraindicate that the concomitant administration of aspirin and certain antibiotics.